They can be triggered by an abnormal immune response to the tumour, or by substances secreted by the neoplasm itself.
The commonest paraneoplastic syndromes are

1. hypercalcemia - mostly due to PTHrP production
2. Cushing's syndrome - ectopic ACTH production
3. non bacterial thrombotic endocarditis - hypercoagulability.

• small cell lung cancer - PNS are most commonly associated with lung cancer. (PNS is reported in 1 in 10 patients with lung CA)

Paraneoplastic antibodies

anti-Hu antibody indicates the presence of a small cell lung cancer and the anti-Yo antibody, the presence of an ovarian or breast cancer.
Source

1. Inflammation of the limbic system (hippocampus, amygdala, hypothalamus, cingulate gyrus, limbic cortex) causes subacute (days to months) *progression of neuropsychiatric symptoms* - mood, memory, cognitive function and seizures. EEG and MRI support diagnosis. Can improve with immunotherapy.

#2022BSQ-MAY QQ18

Cancer cachexia

Loss of lean body mass and fat, with anorexia.
Not caused by energy demand of the cancer or malnutrition.
Rather, it's caused by cytokines (TNF-alpha) released by the cancer.

Cushing's syndrome and Cushing's disease

Features of Cushing's syndrome

1. Osteoporosis
2. Hypertension
3. Facial plethora, proximal myopathy, striae, easy bruising

Commonest cause is iatrogenic;
All glucocorticoids suppress ACTH -> ACTH, and serum cortisol will be low in iatrogenic cushing's syndrome.

The diagnosis of Cushing syndrome is established when at least two different first-line tests are unequivocally abnormal, and physiologic hypercortisolism has been excluded

Sequence of evaluation:

If a patients has feature of Chushing's syndrome

1. It has to be proved that the patient has elevated cortisol
2. The cause of elevated cortisol must be determined.

Initial testing to confirm elevated cortisol:

1. bedtime salivary cortisol

   1. There is a pre-bed time cortisol level nadir in normal physiology.
   2. This is preserved in physiologic hypercortisolism but absent in Cushing's syndrome.

2. 24 hour urinary free cortisol - Measures the total daily cortisol production without being affected by the cyclical variations in it's production.

3. Low dose DST

   1. The low-dose DSTs are standard screening tests to differentiate patients with Cushing syndrome of any cause from patients who do not have Cushing syndrome.
   2. A positive low dose DST will show impaired suppression of cortisol secretion.
   3. The high-dose DSTs are not used to make the diagnosis of Cushing syndrome. (High dose DST is used to identify the source of ACTH if it is abnormally high (i.e Cushing's disease Vs. ectopic ACTH)
   4. There are two forms of low dose DST
      1. Overnight 1mg dexamethasone suppresion test
      2. two day 2 mg DST
   5. Both will show impaired suppression of cortisol if the patient has Cushing's syndrome.

For bedtime salivary cortisol and UFC, two abnormal tests are required.

Pseudo-Cushing's syndrome

If cortisol is found to be elevated with the above preliminary tests, next step is to exclude physiologic hypercortisolism.
AKA - pseudo Cushing syndrome.

Clinically, these patients usually do not have skin or muscle manifestations of Cushing Syndrome.
Causes of pseudo-cushing syndrome (i.e causes of elevated cortisol)

1. #Pregnancy
2. Severe obesity / PCOS
3. Severe major depression
4. Poorly controlled DM
5. OSA

Because of various nuances, the above tests must be unequivocally elevated in order to diagnose Cushing's syndrome. Mild elevations are unlikely to indicate Cushing's syndrome.

Determining the cause of hypercortisolism

Once hypercortisolism has been identified and physiologic hypercortisolism as been excluded, the cause of hypercortisolism must be determined.

First step is determining if the cortisol hypersecretion is
ACTH dependent or ACTH independent.
This is done by measuring ACTH levels.

ACTH levels

Because of cyclical variations, testing at two different times is recommended.

ACTH < 5pg/ML = ACTH independent hypercortisolism

ACTH > 20pg/mL = ACTH dependent hypercortisolism.

ACTH dependent Hypercortisolism

1. The vast majority have pituitary corticotroph adenoma -(CUSHING'S DISEASE)
2. Other causes are ectopic ACTH and ectopic CRH.

Determining the cause of ACTH dependent hypercortisolism

1. CRH stimulation test - differentiates Cushing's disease from all other causes of hypercortisolism
   1. Corticotroph pituitary tumours respond to CRH (despite being tumours) -> AC
2. High dose dexamethason suppression test
   1. Corticotroph tumours are not resistant to negative FB by glucocorticoids
   2. Ectopic ACTH producing tumours have absolutely no inhibition from glucocorticoids. (with the exception of some pulmonar neuroendocrine tumours)
   3. Therefore, 8mg of Dexamethasone oral at 11PM will cause reduction in morning Serum cortisol.
3. Desmopressin stimulation test
   1. Used clinically when CRH is not available
   2. ADH stimulates ACTH release.
   3. Desmopressin is used to mimic this effect. (ADH and desmopressing have a similar action to CRH)
      1. In ACTH secreting adenoma (Cushing's disease) this response is preserved but in ectopic ACTH secreting lesions this response is absent.

Imaging

A mass > 6mm in size in the sella turcica supports a diagnosis of Cushing's disease.
10% of healthy people have masses <6mm in size.

Invasive testing

Sampling the ACTH level from the petrosal sinus can be used if the diagnosis is uncertain.

Unconjugated hyperbilirubinaemia can be cause by ileal resection because decreased resorption of bile salts allows them to enter the colon and solubilize the bilirubin

Gastric cancer

Gastric cancer has poor prognosis and new treatment modalities are needed.

Pathogenesis:
Gastrin, produced by G cells of the antral glands promote growth of gastric adenocarcinoma through cholecystokinin-B receotors which are over expressed in this cancer.
Serum gastrin levels may be increased secondary to
1. chronic administration of proton pump inhibitors,
2. atrophic gastritis,
3. Helicobacter pylori infection,
4. or from de novo gastrin expression from the gastric cancer epithelial cells

[[Hormone Physiology]]

• In adults, bone mets are far more common than primary bone tumours.

• Bone is the 3rd commonest site of metastatis next to Lung and liver.

• Prostate and breast cancer (BC) are responsible for the majority of the skeletal metastases (up to 70%).

• Other sources of bone mets : thyroid, renal cell carcinoma, lung cancer, melanoma

Osteolytic :

1. Multiple myeloma
2. RCC
3. melanoma
4. NSCLC
5. Non Hodgkin Lymphoma
6. thyroid cancer
7. Breast cancer

Osteobastic:

1. prostate cancer,
2. carcinoid,
3. small cell lung cancer,
4. Hodgkin lymphoma
5. medulloblastoma.

Ignore breast in this list!

Breast cancer - The great majority of breast CA produces osteolytic bone lesions, osteoblastic areas are also usually present

Vasculitides / Vasculitis

Main groups of vasculitis

    1. Goodpastures's

Large vessel vasculitides

• Involves the aorta and the major tributaries
• Granulomatous diseases

Polymyalgia rheumatica

Patient it always > 50 years old; sudden onset pain and stiffness (but not weakness) of limb girdles / proximal muscles, associated with raised inflammatory markers.
ALP and gamma GT may be elevated.
Giant cell arteritis is seen in 30% of cases.

Giant cell arteritis

Patient has usually had past or current PMR. (age always > 50)
Treatment should commence immediately.
Giving steroids is essential, since it can prevent vision loss due to ophthalmic artery ischemia.
Steroid should be given in much higher doses than PMR.
High dose steroid therapy can cause osteoporosis.

Takayasu arteritis

Affects the largest vessels in the body: the aorta and it's branches.
Mostly affects women of childbearing age!

Complete obstruction of left common carotid.
(eg, bruit, especially carotid; blood pressure difference of extremities, difference in pulse volume claudication, hypertension)
Steroids are the mainstay.

Medium vessel vasculitides

• medium and small sized arteries and arterioles (mnemonic: i.e the small arteries which have names).

Small vessel vasculitides

• small arteries, arterioles, venules and capillaries (mnemonic: the ones which are too small to name)

Initially, bacilli enter macrophages and prevent formation of the phagolysosome. So they initially proliferate within macrophages.

Development of cell mediated immunity takes about 3 weeks.

1. tuberculous meningitis,
   2. Tuberculous myelitis is acute segmental spinal cord inflammation that may occur in the setting of tuberculosis disease; it may occur in the presence or absence of tuberculous meningitis.
   Vasculitis produced by the exudate can cause obliterative endarteritis.
   This can cause infarctions in the deep structures of the brain.
   Exudate is seen at the base of the brain.

Pathology of tuberculous meningitis

Context

Meningitis can be classified as acute, aseptic (viral) and chronic.
Chronic meningitis include Tuberculous, spirochetal and cryptococcal.

Acute bacterial meningitis

Neonates -> E coli.
Adolescents -> Neisseria meningitides
Older adults and elderly -> Streprococcus pneumoniae and Listeria monocytogenes.

Pathology

Pus fills the subarachnoid space; it may invade the brain by tracking along veins in severe cases (or cause ventriculitis)

Chronic meningitis : Tuberculous meningitis

Clinical: subacute (few weeks) of headache, fever, vomiting, altered sensorium.
Cranial nerve palsies
Mononuclear cells present on CSF analysis.
Massively elevated CSF protein.
Can cause arachnoid fibrosis -> [[Neurology Miscellaneous#Subarachnoid space|hydrocephalus]].
subarachnoid space contains a gellatinous, fibrous exudate.
Microscopy: lymphocytes, macrophages, granulomas, caseous necrosis.
Obliterative endarteritis of vessels passing in the Subarachnoid space.
Hyponatremia is another complication.